In this application for a K01 mentored research award, Dr. Ida Hatoum proposes a comprehensive research and training plan that will incorporate the fields of computational biology, statistics, and physiology. Dr. Hatoum is a postdoctoral fellow at Massachusetts General Hospital (MGH) and Harvard Medical School (HMS) with a background in clinical and genetic epidemiology. This K01 award will provide Dr. Hatoum with the support to receive the training in computational biology and bioinformatics necessary to successfully transition to research independence. She proposes to achieve this through the completion of a MMSc degree program in Computational Bioinformatics at HMS, additional formal coursework, research experience, and interactions with her primary mentor Dr. Lee Kaplan, Director of the MGH Weight Center and MGH Obesity, Metabolism, and Nutrition Institute; her co-mentor Dr. Robert Gerszten of MGH, HMS and the Broad Institute of Harvard and MIT; and her collaborator Dr. Thomas Wang of MGH and HMS. Roux-en-Y gastric bypass (RYGB) is currently one of the most effective long-term therapies for obesity. The recognition that RYGB works through physiological, rather than mechanical, mechanisms provides the opportunity for the discovery of obesity therapies that target the physiological underpinnings of the response to RYGB. Researchers have begun to characterize changes in both humans and rodents after RYGB, but targeted interrogation of key metabolic pathways have not yet been able to fully account for the pleiotropic effects of this procedure. There is therefore currently a significant gap in knowledge between the observed clinical effects of RYGB and the physiological mechanisms underlying this response. Dr. Hatoum's research will address this gap using high-throughput, high-coverage methods to identify significantly regulated genes and pathways with a high likelihood of relevance for the response to RYGB. [In addition, she will functionally assess a candidate gene that was identified through early computational analyses.] Dr. Hatoum [has analyzed] gene expression microarrays in 15 tissues of RYGB-treated mice, including liver, muscle, brain, and multiple segments of the gastrointestinal tract, and compared these profiles to sham- operated weight-matched mice to identify genes associated with RYGB, independent of the effects of weight loss. [Using this approach, she identified LCN2 as a strong candidate for functional follow-up (Specific Aim 1).] While the study of mice allows for experimental control, the relevance of the mouse model of RYGB to the human operation must be verified. However, the analysis of gene expression in most biologically relevant tissues is too invasive for study in living (human) participants. Therefore, Specific Aim [2a] will utilize a nonhuman primate (NHP) model of RYGB to validate the genes identified in [preliminary analyses] and determine the likely relevance of these genes to human physiology. In Specific Aim 2b, Dr. Hatoum will analyze the blood metabolic profiles of human patients pre- and post-RYGB to further refine the set of candidate genes and pathways. Integration of the complementary approaches of comprehensive gene expression analysis and metabolomics will allow for the identification of strong functional candidates with relevance to human physiology. We hypothesize that the genes and pathways identified through this novel multi-stage approach will represent the set of genes that are both functionally indicative of the effects of RYGB independent of weight loss and that have relevance to humans. The identification of the physiological mechanisms of action of this procedure may help aid in the development of less invasive therapies for obesity and provide valuable information about the mechanisms of weight regulation more broadly.